Diphenhydramine, hydrochloride (Benadryl.RTM., or 2-(diphenylmethoxy) N, N-dimethylethylamine), is known to be useful for its antihistaminic, anticholinergic, antitussive, antiemetic, and sedative properties The compound and its preparation are described in U.S. Pat. No. 2,421,714 which is hereby incorporated by reference.
The base is a liquid and its salts have acceptable solubilities in standard liquid media. Thus, diphenhydramine-based drugs are conventionally used in dosage forms such as oral and parenteral. However, there are undesirable digestive side effects possible with oral formulations. Generally there are compliance problems with parenterals.
Diphenhydramine is a nonprescription drug widely used alone or in combination with other drugs as an effective antihistamine with a sedative side effect. Carruthers, et al (Clin Pharmacol Ther 1978; 23:375-382) showed that the sedative side effect of diphenhydramine hydrochloride could be eliminated if the blood concentration remains in the range of 25 to 50 ng/ml (equivalent to 21.9 to 43.9 ng/ml diphenhydramine base). This indicates that a sustained dosage form which could provide such constant blood levels would be a very useful and viable dosage form in the treatment of allergy.
Tetrahydroaminoacridine (1,2,3,4-tetrahydro-9-acridinamine, tacrine, or THA) is a very old compound known to have anticholinesterase activity. It has been shown that THA improves the amnesia characteristic of Alzheimer's disease (Brinkman and Gershon, 1983; Flood et al, 1985; Rathman and Conner, 1984; McGeer, 1984).
Tazifylline is known to be useful as an antihistamine. It is covered in U.S. Pat. No. 4,374,835 which is hereby incorporated by reference.
Atenolol, 4-[2-hydroxy-3-[(1-methylethyl)amino]propoxy]benzeneacetamide, is covered in U.S. Pat. Nos. 3,663,607 and 3,836,671 hereby incorporated by reference. It is a .beta.-adrenergic blocker.
2-Methoxy-4-[2-(5-methyl-1H-pyrazol-3-yl)ethenyl]phenol is covered in pending application 861,179. It has antiasthma, antiallergy, antiinflammatory, antipsoriatic, analgesic, and cardiovascular activities.
Diltiazem and verapamil are coronary vasodilators (calcium antagonists) covered by U.S. Pat. Nos. 3,562,257 and 3,261,859.
Hydrocortisone is an adrenocortical steroid and is useful as a topical antiinflammatory. Hydrocortisone and methods for preparing it are covered in U.S. Pat. No. 2,602,769.
While the above drugs are highly efficacious, their use is subject to such problems as dose dumping and high drug use requirements.
U.S. Pat. No. 4,611,008 discloses the use of Miglyol-812 or Miglyol-829 in a coronary-active gel-containing preparation.
U.S. Pat. No. 4,331,651 covers in part, caprylic/capric acid -1,2-propanediol diester used as a release-promoting substance used in a silicone rubber carrier for an active ingredient.
U.S. Pat. No. 4,336,243 covers a microsealed transdermal delivery pad for nitroglycerin administration which contains a silicon matrix having microsealed compartments of silicone rubber mixed with a hydrophilic solvent system, the solvent system can contain a saturated coconut oil such as miglyol oil which improves the transport and absorption of the nitroglycerin.
U.S. Pat. No. 4,788,063 covers a transdermal pharmaceutical composition for delivery of cholinergic and anticholinergic basic drugs. The active ingredients are in a vehicle such as a lower fatty acid which serves as a solvent and a transdermal delivery agent.
U.S. Pat. No. 4,485,087 covers a process for preparing a composite pharmaceutical preparation.
European Application 243891 covers a laminar structure for administering a chemical at a controlled rate.